Limits...
Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism

View Article: PubMed Central - PubMed

ABSTRACT

Parathyroid hormone (PTH) is essential for calcium homeostasis and its action is mediated by the PTH type 1 receptor (PTHR1), a class B G-protein-coupled receptor. Hypoparathyroidism and osteoporosis can be treated with PTH injections; however, no orally effective PTH analogue is available. Here we show that PCO371 is a novel, orally active small molecule that acts as a full agonist of PTHR1. PCO371 does not affect the PTH type 2 receptor (PTHR2), and analysis using PTHR1–PTHR2 chimeric receptors indicated that Proline 415 of PTHR1 is critical for PCO371-mediated PTHR1 activation. Oral administration of PCO371 to osteopenic rats provokes a significant increase in bone turnover with limited increase in bone mass. In hypocalcemic rats, PCO371 restores serum calcium levels without increasing urinary calcium, and with stronger and longer-lasting effects than PTH injections. These results strongly suggest that PCO371 can provide a new treatment option for PTH-related disorders, including hypoparathyroidism.

No MeSH data available.


Related in: MedlinePlus

Synthesis of PCO371.Reagents and conditions: (a) 4-trifluoromethoxybenzoic acid, HATU, DIPEA and DMF, room temperature; (b) 30% H2O2 aq., 2 mol l−1 NaOH aq., EtOH, room temperature, then 5 mol l−1 NaOH aq., 50 °C; (c) 4 mol l−1 HCl in dioxane, CH2Cl2, room temperature; (d) 2-chloroethane-1-sulfonyl chloride, Et3N, CH2Cl2, room temperature. (e) 1-(4-bromo-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione, Pd(dba)2, t-Bu3P-HBF4, methyl dicyclohexylamine, NMP, 100 °C; (f) 20% Pd(OH)2/C, H2, DMF–MeOH–MeCN, room temperature.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5120204&req=5

f7: Synthesis of PCO371.Reagents and conditions: (a) 4-trifluoromethoxybenzoic acid, HATU, DIPEA and DMF, room temperature; (b) 30% H2O2 aq., 2 mol l−1 NaOH aq., EtOH, room temperature, then 5 mol l−1 NaOH aq., 50 °C; (c) 4 mol l−1 HCl in dioxane, CH2Cl2, room temperature; (d) 2-chloroethane-1-sulfonyl chloride, Et3N, CH2Cl2, room temperature. (e) 1-(4-bromo-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione, Pd(dba)2, t-Bu3P-HBF4, methyl dicyclohexylamine, NMP, 100 °C; (f) 20% Pd(OH)2/C, H2, DMF–MeOH–MeCN, room temperature.

Mentions: Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification (Fig. 7). Silica gel chromatography purification was performed using prepacked silica gel cartridges (Biotage, Shoko Scientific). Reverse-phase column chromatography purification was performed using Wakosil 25C18 (Wako Pure Chemical Industries). Nuclear magnetic resonance (NMR) spectra were determined with a Varian MR-400 spectrometer (400 MHz, Agilent).


Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism
Synthesis of PCO371.Reagents and conditions: (a) 4-trifluoromethoxybenzoic acid, HATU, DIPEA and DMF, room temperature; (b) 30% H2O2 aq., 2 mol l−1 NaOH aq., EtOH, room temperature, then 5 mol l−1 NaOH aq., 50 °C; (c) 4 mol l−1 HCl in dioxane, CH2Cl2, room temperature; (d) 2-chloroethane-1-sulfonyl chloride, Et3N, CH2Cl2, room temperature. (e) 1-(4-bromo-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione, Pd(dba)2, t-Bu3P-HBF4, methyl dicyclohexylamine, NMP, 100 °C; (f) 20% Pd(OH)2/C, H2, DMF–MeOH–MeCN, room temperature.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120204&req=5

f7: Synthesis of PCO371.Reagents and conditions: (a) 4-trifluoromethoxybenzoic acid, HATU, DIPEA and DMF, room temperature; (b) 30% H2O2 aq., 2 mol l−1 NaOH aq., EtOH, room temperature, then 5 mol l−1 NaOH aq., 50 °C; (c) 4 mol l−1 HCl in dioxane, CH2Cl2, room temperature; (d) 2-chloroethane-1-sulfonyl chloride, Et3N, CH2Cl2, room temperature. (e) 1-(4-bromo-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione, Pd(dba)2, t-Bu3P-HBF4, methyl dicyclohexylamine, NMP, 100 °C; (f) 20% Pd(OH)2/C, H2, DMF–MeOH–MeCN, room temperature.
Mentions: Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification (Fig. 7). Silica gel chromatography purification was performed using prepacked silica gel cartridges (Biotage, Shoko Scientific). Reverse-phase column chromatography purification was performed using Wakosil 25C18 (Wako Pure Chemical Industries). Nuclear magnetic resonance (NMR) spectra were determined with a Varian MR-400 spectrometer (400 MHz, Agilent).

View Article: PubMed Central - PubMed

ABSTRACT

Parathyroid hormone (PTH) is essential for calcium homeostasis and its action is mediated by the PTH type 1 receptor (PTHR1), a class B G-protein-coupled receptor. Hypoparathyroidism and osteoporosis can be treated with PTH injections; however, no orally effective PTH analogue is available. Here we show that PCO371 is a novel, orally active small molecule that acts as a full agonist of PTHR1. PCO371 does not affect the PTH type 2 receptor (PTHR2), and analysis using PTHR1–PTHR2 chimeric receptors indicated that Proline 415 of PTHR1 is critical for PCO371-mediated PTHR1 activation. Oral administration of PCO371 to osteopenic rats provokes a significant increase in bone turnover with limited increase in bone mass. In hypocalcemic rats, PCO371 restores serum calcium levels without increasing urinary calcium, and with stronger and longer-lasting effects than PTH injections. These results strongly suggest that PCO371 can provide a new treatment option for PTH-related disorders, including hypoparathyroidism.

No MeSH data available.


Related in: MedlinePlus